1. Field of Invention
The invention relates to a method for operating a laser. In particular, it relates to a method of operating a laser having dosimetry control for use in ophthalmic medicine, but also in general therapy of biological tissue.
2. Description of the Prior Art
In ophthalmology, laser systems are widely used both in correcting visual acuity (e.g. corneal ablation) and also in the therapy of retinal diseases. Lasers work well for this purpose due to the transparency of the eye for visible light.
Special interests exist in connection with the treatment of the dysfunction of “retinal pigmentary epithelium” (RPE), a highly pigmented monocellular layer between the choroid and retina of the eye. The highly multifunctional RPE, inter alia, governs the metabolism of photoreceptors, the liquid management of the retina and the phagocytosis of rhodopsin disks, the catabolites of the vision process. With increasing age, metabolic end products of constant receptor regeneration are accumulated in the RPE (inter alia lipofuscins), which leads to a continuously decreasing function of this cellular layer.
For example, senile macular degeneration (SMD) with rising incidence is the most frequent visual deprivation cause in people over 50 years old in industrial countries. According to the Framingham eye study, 2% of persons between the ages of 52 and 64 are affected by SMD, between 65 and 74 11%, and over a third of all people between the ages of 75 and 84 are affected with SMD. In the USA alone there was an estimate that there were 4 to 10 million patients in the year 2000.
The second most frequent cause of visual deprivation is diabetic retinopathy (DR), which is a late consequence of diabetes mellitus. With increasing duration of the disease, there is a rise in the frequency of retinal changes and after 30 years this rises to virtually 100%. Due to rises in human age, ever increasing importance is attached to early, efficient and careful therapy of SMD and DR. Retinal pigmentary epithelium is at least involved in the occurrence of SMD or DR, because vascularizations and edemas arise in the area round the RPE, which should not occur with a functionally intact RPE.
Fundamentally, no problems arise in the laser treatment of dysfunctional RPE, particularly in the early stage of the disease. Irradiation of targeted diseased areas of the eye fundus are admittedly thermally sclerosed and, as a result of the subsequent regeneration and lateral proliferation of RPE cells in the sclerotic zones, there are good prospects of a substantial restoration of the intact RPE. However, the production of temperatures lethal to the diseased cells through laser light absorption gives rise to potentially further damage to the surrounding tissue, which can lead to the necrosis of the non-regenerating photoreceptors and therefore to permanent loss of vision.
Selective RPE therapy (SRT), which by definition avoids damage to the RPE environment, is at present undergoing considerable development and has good prospects of establishing itself as a widespread therapy method in the near future. However, this presupposes that an optimized, easily handled laser system is marketed. The method of the present invention, inter alia, is intended to contribute to, and thus improve upon, such therapy.
According to the proposal of DE 39 36 716 C2, for the selective influencing of a good absorbing material in a matrix with a lower absorption capacity, repeat irradiation is recommended, such as the application of pulsed laser radiation. The rapidly succeeding arrival of a plurality of light pulses allows for heating of the target substance, which otherwise could only be obtained with a single pulse with a much higher energy. However, the time splitting of energy deposition, at the same time, allows for the utilization of heat and energy transport mechanisms in the material. The area heated in critical manner by the light is closely limited to the area around the target structures.
In the application of this concept to SRT, at present, a burst, i.e. a pulse sequence, of approximately 30 laser pulses with a pulse duration, in each case, of 1.7 μs in the green spectral range and with a pulse sequence rate of 100 Hz at a wavelength of 527 nm is used. Natural and numerous variations to these treatment parameters are also possible. For the thermotherapy of biological tissue, particularly of the eye fundus, clear preference is given to pulse durations of a few microseconds. The production of such laser pulses with an approximately constant pulse power is described in DE 44 01 917 C2. As a result of the strong pigmentation of the RPE (approximately 50% of the incident light in the green spectral range is absorbed by the pigment granules (melanosomes) in the RPE cells) high temperatures occur in the RPE in the case of corresponding irradiation (approx. 600 mJ/cmý per pulse), which lead to intracellular micro-vaporization on the strongly heated RPE melanosomes.
The resulting micro-bubbles for μs increase the cell volume and in all probability ultimately lead to the disruption and disintegration of the RPE cell. The irradiation threshold for cell damage can drop significantly through the application of multiple pulses.
A laser system for eye treatment which monitors the average pulse energy of the emitted radiation using sensors and controls the same by feedback, i.e. to a predefined value is described in WO 91/19539 A1. The intended protection of healthy cells is as little ensured with such a system as the therapeutic activity thereof. Thus, there is a considerable variation between patients concerning the prerequisites for laser therapy (e.g. transparency of the lens or glass body, pigmentation of the retina) in connection with eye fundus treatment.
Research results show that the necessary pulse energies for producing RPE effects fluctuate intra-individually by up to 100% and inter-individually to an even greater extent. Existing experience shows that the pulse energy must be no more than a factor of two above the threshold pulse energy for producing RPE damage, or otherwise visible damage occurs to the retina. However, a previously made choice regarding the laser energy for the same reason can be too low in order to influence the RPE, which renders the invention ineffective.
Checking the results of RPE damage can at present only take place after the end of treatment under clinical conditions. For dosimetry control, a fluorescence angiography of the eye fundus takes place after the operation. To this end, a dye (fluorescent or ICG) is injected into the bloodstream of the patient and diffuses from the choroid through the damaged RPE to the retina and in this way demarcates RPE defects during fundus fluorescence photography. However, this invasive procedure cannot be carried out in standard ophthalmic practices and consequently, at present, the therapy is restricted to well equipped clinics or university eye hospitals. Particularly with inadequate treatment results up to the decomposition of the dyes, there can be no direct continuation of the treatment and the fundamentally toxic action thereof often requires a long therapy interval. Thus, what is important for an effective, but protective treatment is the continuous observation of the radiation action on the tissue during the operation.
The already described destruction of RPE cells by thermal disruption forms the basis for DE 199 32 477 A1 C2 for the detection of RPE damage on the basis of mechanical deformations. The short-term expansion of irradiated RPE cells during the formation of gas bubbles (micro-vaporization) directly associated with RPE destruction can be acoustically measured and used for controlling a treatment laser. Below the pulse energy threshold necessary for bubble formation, the material response is thermo-elastic and reproducible, i.e. each incident pulse produces a pressure wave which, starting from the eye fundus, passes through the eyeball and as a function of time can be recorded with a transducer (e.g. an annular piezo-ceramic in a contact lens). Two successively applied, identical pulses produce identical pressure transients at the same material location. The amplitudes of the pressure transients are approximately linear to the pulse energy, provided that this remains below the bubble formation threshold.
On exceeding the threshold, the pressure amplitude rises in a super-proportional manner. The course of the transients changes between individual pulses, even with otherwise constant pulse shape and energy of the applied radiation due to the statistics of the use of micro-vaporization on melanin granules. In this way, the therapeutically effective pulse energy can be precisely determined and acts on the RPE cells, but leaves the surrounding area largely unaffected.
Initial treatments of patients have, in the meantime, shown that the opt-acoustic check is highly suitable to directly detect micro-vaporization on-line following laser burst application. Information up to now shows that the result is eminently correlated with the fluorescence angiographically established RPE leaks, in each case, determined following the treatment.
The resulting acoustic transients are measured with the aid of a sound transducer integrated into the contact lens. This does not impair the treatment, because contact lenses are in any case required for compensating the refraction of light of the eye media. The acoustic signals are pre-amplified, transferred to a PC and calculated.
The result in the form of a single number is indicated directly following the application of the burst and immediately informs the surgeon whether the pulse energy was adequate for RPE effects at the point just treated. If not, it is immediately possible to again apply a burst with a higher pulse energy.
A principal disadvantage of this procedure is its complicated nature, in that the surgeon may have to irradiate the same area with an increasing pulse energy until an RPE effect occurs. This also gives rise to the problem of the precise position of the application location on the retina. If a certain time elapses between the measurement of the energy requirement and the actual therapy irradiation, even minor eye movements can lead to therapy of the retina taking place at a different location. As a result of the aforementioned in homogeneity of the energy requirements for RPE damage, even in the eye of the same patient, this can cast doubts both on the success of the therapy and the avoidance of collateral damage. In addition, the irradiated area on the retina cannot be irradiated again, because the radiation application location is invisible to the surgeon, independently of the result of the irradiation, because an eye never remains stationary for more than a few seconds.
The optical detection of micro-vaporization on the retina is described in WO 01/91661 A1, use being made of the back-reflection of treatment or test laser light which increases with bubble formation.
Neither in WO 01/91661 A1 nor in the already cited DE 199 32 477 A1 are provided algorithms or information for controlling the treatment laser making it possible to treat all retina locations in the case of widely varying threshold values for RPE effects close to said threshold. It has been clinically shown that the threshold-near irradiation is absolutely necessary for selective RPE effects, because otherwise retinal damage occurs.
Initial results of research by the inventor have revealed that on individual patient treatment of energy thresholds between 200 and 350 μJ/pulse, the retinal damage thresholds (optical visibility of effects) are 300 μJ in areas with a low threshold. Thus, pulse energy leading to no effects in some areas, leads to visible retinal damage in other areas.
It is therefore desirable to carry out a control of the treatment laser in such a way that irradiation just above the threshold for RPE damage is possible in order to minimize the risks of serious side effects. Multiple radiation application per irradiation location is to be avoided. The surgeon should only have to irradiate once and needs to be sure that the desired RPE effects occur.
The task of searching for a therapeutically effective pulse energy no longer has to be carried out separately. It can reliably be assumed that the treatment is effective. This is particularly important for the widespread use of such treatment lasers in each ophthalmic practice, where the aforementioned methods for checking the results could not be performed other than with high costs or where the specialist would otherwise need special laser control training.
Therefore, the problem of the invention is to provide a method for operating an irradiation laser, in which laser pulse sequences or varying longer pulses, during application, are modified in such a way that the comparability of detected transients is maintained.